Dynamic allostery-based molecular workings of kinase:peptide complexes

Abstract

A dense interplay between structure and dynamics underlies the working of proteins, especially enzymes. Protein kinases are molecular switches that are optimized for their regulation rather than catalytic turnover rates. Using long-simulations dynamic allostery analysis, this study describes an exploration of the dynamic kinase:peptide complex. We have used protein kinase A (PKA) as a model system as a generic prototype of the protein kinase superfamily of signaling enzymes. Our results explain the role of dynamic coupling of active-site residues that must work in coherence to provide for a successful activation or inhibition response from the kinase. Amino acid networks-based community analysis allows us to ponder the conformational entropy of the kinase:nucleotide:peptide ternary complex. We use a combination of 7 peptides that include 3 types of PKA-binding partners: Substrates, products, and inhibitors. The substrate peptides provide for dynamic insights into the enzyme:substrate complex, while the product phospho-peptide allows for accessing modes of enzyme:product release. Mapping of allosteric communities onto the PKA structure allows us to locate the more unvarying and flexible dynamic regions of the kinase. These distributions, when correlated with the structural elements of the kinase core, allow for a detailed exploration of key dynamics-based signatures that could affect peptide recognition and binding at the kinase active site. These studies provide a unique dynamic allostery-based perspective to kinase:peptide complexes that have previously been explored only in a structural or thermodynamic context.

A single amino acid substitution uncouples catalysis and allostery in an essential biosynthetic enzyme in Mycobacterium tuberculosis

“…Dynamic allostery or entropically-driven allostery has been extensively studied in recent years, with its intriguing functional responses accompanied with the apparent lack of observable structural changes. [33][34][35][36][37][38][39][40][41][42] Dynamic allostery is an intrinsic property of enzymes and is intimately linked with catalysis. 34,39,42,43 In this study, we identified a key node embedded in an intricate and extensive allosteric network, which is remote to any ligand binding site.…”

Human carbonic anhydrases and post-translational modifications: a hidden world possibly affecting protein properties and functions

“…This was expected based on the general globular characteristics of the CA domain and the post-translational nature of the considered modification, which is determined by the action of specific kinases on the folded protein. Exceptions were associated with the possible occurrence of molecular events related to the local unfolding action of kinases on CA flexible portions to be modified 44 , or the direct action of above-mentioned phosphorylating enzymes on degraded and/or unfolded molecular species 45 . In general, all phosphorylated amino acids occurred far away from the catalytic cavity.…”

Identification of tyrosine kinase inhibitors that halt Plasmodium falciparum parasitemia

“…Upon completion of our blinded analysis of the effects of these PTK inhibitors analogs on parasite maturation, we submitted our ranked list of the 10 most potent anti-malaria kinase inhibitors to our Eli Lilly collaborators for annotation with chemical identities and primary kinase target identification [36,[45][46][47][48][49][50]. Data from the annotation revealed that all potent inhibitors of P. falciparum egress at the segmenter stage as well as inhibitors of diamide and o-vanadate induced band 3 tyrosine phosphorylation ( Fig 4B) display Syk tyrosine kinase inhibitory activity.…”